Abstract
IMPORTANCE: As genetic and genomic screening is becoming more widely accessed, correctly distinguishing pathogenic from nonpathogenic variants is of increasing relevance. OBJECTIVE: To reevaluate a previously reported family in whom the p.(Pro50Leu) variant in the gene GUCA1A was associated with a dominant retinal dystrophy, in light of new examination findings in the proband's daughter. DESIGN, SETTING, AND PARTICIPANTS: A genetic study relating to a family with an inherited retinal dystrophy was performed at the retinal genetics service of Moorfields Eye Hospital from October 27, 2009, to May 23, 2019, after the proband's daughter underwent fundus examination. MAIN OUTCOMES AND MEASURES: Results of sequencing of X chromosome-linked retinitis pigmentosa genes in the proband and specific analysis of the repetitive ORF15 region of the RPGR gene. RESULTS: A frame-shifting single-nucleotide deletion was found in the ORF15 exon of RPGR (GRCh37 [hg19] x:38145160delT; NM_001034853.1: c.3092delA p.[Glu1031Glyfs*58]), which may be associated with the loss of 121 amino acid residues at the carboxyl terminus of the protein. The p.(Pro50Leu) variant in GUCA1A was also found to be too common in a publicly available genome database to be a fully penetrant cause of a dominant retinal dystrophy. CONCLUSIONS AND RELEVANCE: The phenotype in the family is now associated with the variant in RPGR. The findings suggest that the p.(Pro50Leu) variant in GUCA1A should not be regarded as pathogenic. This report also highlights the relevance of examining relatives, of reevaluating diagnoses in light of new data, and of considering X chromosome-linked inheritance in apparently autosomal dominant pedigrees unless there is clear male-to-male transmission.